Normalized unitary synaptic signaling of the hippocampus and entorhinal cortex predicted by deep learning of experimental recordings.

Biologically realistic computer simulations of neuronal circuits require systematic data-driven modeling of neuron type-specific synaptic activity. However, limited experimental yield, heterogeneous recordings conditions, and ambiguous neuronal identification have so far prevented the consistent characterization of synaptic signals for all connections of any neural system. We introduce a strategy to overcome these challenges and report a comprehensive synaptic quantification among all known neuron types of the hippocampal-entorhinal network. First, we reconstructed >2600 synaptic traces from ∼1200 publications into a unified computational representation of synaptic dynamics. We then trained a deep learning architecture with the resulting parameters, each annotated with detailed metadata such as recording method, solutions, and temperature. The model learned to predict the synaptic properties of all 3,120 circuit connections in arbitrary conditions with accuracy approaching the intrinsic experimental variability. Analysis of data normalized and completed with the deep learning model revealed that synaptic signals are controlled by few latent variables associated with specific molecular markers and interrelating conductance, decay time constant, and short-term plasticity. We freely release the tools and full dataset of unitary synaptic values in 32 covariate settings. Normalized synaptic data can be used in brain simulations, and to predict and test experimental hypothesis.

Metabolic design in a mammalian model of extreme metabolism, the North American least shrew (Cryptotis parva).

Mitochondrial adaptations are fundamental to differentiated function and energetic homeostasis in mammalian cells. But the mechanisms that underlie these relationships remain poorly understood. Here, we investigated organ-specific mitochondrial morphology, connectivity and protein composition in a model of extreme mammalian metabolism, the least shrew (Cryptotis parva). This was achieved through a combination of high-resolution 3D focused ion beam electron microscopy imaging and tandem mass tag mass spectrometry proteomics. We demonstrate that liver and kidney mitochondrial content are equivalent to the heart, permitting assessment of mitochondrial adaptations in different organs with similar metabolic demand. Muscle mitochondrial networks (cardiac and skeletal) are extensive, with a high incidence of nanotunnels - which collectively support the metabolism of large muscle cells. Mitochondrial networks were not detected in the liver and kidney as individual mitochondria are localized with sites of ATP consumption. This configuration is not observed in striated muscle, likely due to a homogeneous ATPase distribution and the structural requirements of contraction. These results demonstrate distinct, fundamental mitochondrial structural adaptations for similar metabolic demand that are dependent on the topology of energy utilization process in a mammalian model of extreme metabolism. KEY POINTS: Least shrews were studied to explore the relationship between metabolic function, mitochondrial morphology and protein content in different tissues. Liver and kidney mitochondrial content and enzymatic activity approaches that of the heart, indicating similar metabolic demand among tissues that contribute to basal and maximum metabolism. This allows an examination of mitochondrial structure and composition in tissues with similar maximum metabolic demands. Mitochondrial networks only occur in striated muscle. In contrast, the liver and kidney maintain individual mitochondria with limited reticulation. Muscle mitochondrial reticulation is the result of dense ATPase activity and cell-spanning myofibrils which require networking for adequate metabolic support. In contrast, liver and kidney ATPase activity is localized to the endoplasmic reticulum and basolateral membrane, respectively, generating a locally balanced energy conversion and utilization. Mitochondrial morphology is not driven by maximum metabolic demand, but by the cytosolic distribution of energy-utilizing systems set by the functions of the tissue.

Mitochondrial DNA segregation and replication restrict the transmission of detrimental mutation.

Although mitochondrial DNA (mtDNA) is prone to accumulate mutations and lacks conventional DNA repair mechanisms, deleterious mutations are exceedingly rare. How the transmission of detrimental mtDNA mutations is restricted through the maternal lineage is debated. Here, we demonstrate that mitochondrial fission, together with the lack of mtDNA replication, segregate mtDNA into individual organelles in the Drosophila early germarium. After mtDNA segregation, mtDNA transcription begins, which activates respiration. Mitochondria harboring wild-type genomes have functional electron transport chains and propagate more vigorously than mitochondria containing deleterious mutations in hetreoplasmic cells. Therefore, mtDNA expression acts as a stress test for the integrity of mitochondrial genomes and sets the stage for replication competition. Our observations support selective inheritance at the organelle level through a series of developmentally orchestrated mitochondrial processes. We also show that the Balbiani body has a minor role in mtDNA selective inheritance by supplying healthy mitochondria to the pole plasm. These two mechanisms may act synergistically to secure the transmission of functional mtDNA through Drosophila oogenesis.

Nanocrystalline cellulose applied simultaneously as the gate dielectric and the substrate in flexible field effect transistors.

Cotton-based nanocrystalline cellulose (NCC), also known as nanopaper, one of the major sources of renewable materials, is a promising substrate and component for producing low cost fully recyclable flexible paper electronic devices and systems due to its properties (lightweight, stiffness, non-toxicity, transparency, low thermal expansion, gas impermeability and improved mechanical properties).Here, we have demonstrated for the first time a thin transparent nanopaper-based field effect transistor (FET) where NCC is simultaneously used as the substrate and as the gate dielectric layer in an 'interstrate' structure, since the device is built on both sides of the NCC films; while the active channel layer is based on oxide amorphous semiconductors, the gate electrode is based on a transparent conductive oxide.Such hybrid FETs present excellent operating characteristics such as high channel saturation mobility (>7 cm(2) V (-1) s(-1)), drain-source current on/off modulation ratio higher than 10(5), enhancement n-type operation and subthreshold gate voltage swing of 2.11 V/decade. The NCC film FET characteristics have been measured in air ambient conditions and present good stability, after two weeks of being processed, without any type of encapsulation or passivation layer. The results obtained are comparable to ones produced for conventional cellulose paper, marking this out as a promising approach for attaining high-performance disposable electronics such as paper displays, smart labels, smart packaging, RFID (radio-frequency identification) and point-of-care systems for self-analysis in bioscience applications, among others.

An evaluation of an attempt to change the snacking habits of pre-school children using social marketing.

OBJECTIVES: To demonstrate the feasibility and value of social marketing over a wide geographical footprint, and to improve the snacking habits of pre-school children. STUDY DESIGN: Two cross-sectional studies before and approximately 3 months after a social marketing intervention targeted into the least affluent areas using convenience sampling. METHODS: Based on market research and directed at the least affluent areas, a brand was created ('Snack Right') and an information leaflet was distributed, supported by a media launch and events at children's centres in targeted areas. This evaluation of some aspects of the project is based on a questionnaire delivered before and after the events. RESULTS: There were several differences in pre- and post-event responses consistent with the messages delivered, for example increased spending on fruit (but not vegetables) and more positive attitudes towards fruits and vegetables. Some ambiguities were exposed, for example towards snacking, which have implications for the nutritional knowledge of health professionals. The Snack Right brand was recalled by a very high proportion of respondents at follow-up. CONCLUSIONS: This project has shown that social marketing is a viable tool at a subregional level and has the potential to change attitudes, knowledge and behaviour.

A pilot study on body image, attractiveness and body size in Gambians living in an urban community.

OBJECTIVE: We investigated the attitudinal and perceptual components of body image and its link with body mass index (BMI) in a sample of urban Gambians. We also looked at cross-cultural differences in body image and views on attractiveness between Gambians and Americans. METHODS: Four groups of 50 subjects were assessed: men 14- 25y (YM); women 14-25y (YW); men 35-50y (OM); women 35-50y (OW). Socio-economic status, education, healthy lifestyle and western influences were investigated. Height and weight were measured. Body dissatisfaction was assessed with the body dissatisfaction scale of the Eating Disorder Inventory. Perceptions of body image and attractiveness were assessed using the Body Image Assessment for Obesity (BIA-O) and Figure Rating Scale (FRS). RESULTS: Different generations of Gambians had very different perceptions and attitudes towards obesity. Current body size was realistically perceived and largely well tolerated. Older women had a higher body discrepancy (current minus ideal body size) than other groups (p<0.001). Regression analysis showed they were not worried about their body size until they were overweight (BMI=27.8 kg/m2), whilst OM, YM and YW started to be concerned at a BMI respectively of 22.9, 19.8 and 21.5 kg/m2. A cross-cultural comparison using published data on FRS showed that Gambians were more obesity tolerant than black and white Americans. DISCUSSION: The Gambia is a country in the early stage of demographic transitions but in urban areas there is an increase in obesity prevalence. Inherent tensions between the preservation of cultural values and traditional habits, and raising awareness of the risks of obesity, may limit health interventions to prevent weight gain.

Urbanization and obesity in The Gambia: a country in the early stages of the demographic transition.

OBJECTIVE: To investigate the distribution of overweight and obesity and its relationship with socio-economic and behavioural factors in a developing-country population undergoing rapid nutritional transition. DESIGN: Cross-sectional house-to-house survey in urban Gambia. SUBJECTS: Four groups of 50 subjects were sampled as follows: young men (YM, 14-25 years), young women (YW, 14-25 years), older men (OM, 35-50 years) and older women (OW, 35-50 years). MEASUREMENTS: Several socio-economic and behavioural factors were investigated. Composite indices for socio-economic status, education, healthy lifestyle and western influences were created. Body weight, height, waist and hip circumferences were measured and body mass index (BMI) was calculated. Body composition was assessed by leg-to-leg bioimpedance. Overweight was defined as BMI=25.0-29.9 kg/m(2) and obesity as BMI>or=30.0 kg/m(2). RESULTS: There were highly significant gender and age differences in overweight (YM=0%, YW=10%, OM=6% and OW=34%) and obesity (YM=0%, YW=4%, OM=6% and OW=50%). Only 16% of OW were neither overweight nor obese compared to 88% of OM. OW had a higher fat mass percent (38.4%) than other groups, while fat-free mass (kg) was significantly higher in males than females with YW having the lowest value. Young generations were more educated and more influenced by western ideals than OM and OW. Weight gain was not always associated with weight concern and many overweight/obese subjects did not perceive themselves as overweight. CONCLUSION: Social and behavioural changes are already creating a perceptible 'generational gap' among this population undergoing rapid transition. The improved education and current lean status of the younger adults offers opportunities for preventative interventions. These need to be specially targeted at women.

Increased turnover of CCR5+ and redistribution of CCR5- CD4 T lymphocytes during primary human immunodeficiency virus type 1 infection.

CCR5 is the major coreceptor for human immunodeficiency virus (HIV) type 1 during primary infection. CCR5+ CD4 T lymphocytes were studied in subjects with primary HIV-1 infection (PHI) or acute Epstein-Barr virus (EBV) infection and in HIV-uninfected controls. The early decline of CD4 T lymphocytes during PHI resulted from depletion of CCR5- CD4 T lymphocytes. After antiretroviral therapy, Ki-67- CCR5- CD4 T cell counts rapidly increased in the circulation, which suggests that the initial decrease was due to an alteration in trafficking and/or sequestration. In the CCR5+ subset of CD4 T cells, there was an elevation in the proliferative (Ki-67+) fraction during PHI, yet their total number remained in the normal range. In contrast, in acute EBV infection, proliferating CCR5+ CD4 T cells accumulated to very high levels, suggesting they have an important role in the early antiviral response, which may be impaired in HIV-1 infection.

Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection.

OBJECTIVE: To compare the effect of highly active antiretroviral therapy on immune reconstitution in subjects with acute and chronic HIV-1 infection. DESIGN: Prospective study including 58 treatment-naive subjects who commenced indinavir or nelfinavir and two nucleosides during primary (PHI; n = 28) or chronic HIV-1 infection (CHI; n = 30). METHODS: Naive (CD45RA+ 62L+), memory (CD45RA-) and activated (CD38+ HLA-DR+) T cell subsets were quantified at 1-2 monthly time intervals using 4-colour flow cytometry. RESULTS: At 1 year, HIV-1 RNA declined in both cohorts to undetectable levels (< 50 copies/ml), while median CD4 lymphocyte count increased from 470 to 758 x 10(6) cells/l in PHI and from 204 to 310 x 10(6) cells/l in CHI, reaching > 500 x 10(6) cells/l in 93% of PHI, but only in 37% of CHI subjects (P < 0.001). Naive CD4 lymphocytes increased from 106 to 176 x 10(6) cells/l in PHI and from 41 to 44 x 10(6) cells/l in CHI (PHI versus CHI at 12 months: P = 0.003), while memory cells rose from 368 to 573 x 10(6) cells/l in PHI and from 148 to 223 x 10(6) cells/l in CHI (P < 0.001). Early increases (< 3 months) of CD4 lymphocytes were larger in subjects with PHI, consisting of naive CD45RA+ CD62L+ as well as memory CD45RA- CD62L+ cells (P = 0.001). CD4 activation declined from 5 to 2% in PHI and from 13 to 6% in CHI (P = 0.001), while CD8 cell activation was reduced from 33 to 15% in PHI and from 42 to 19% in CHI (P = 0.02). CONCLUSION: Immune reconstitution was more complete, occurred earlier and comprised both naive and memory CD4 T lymphocytes in subjects who commenced antiretroviral therapy during primary HIV-1 infection.

Potent antiretroviral therapy of primary human immunodeficiency virus type 1 (HIV-1) infection: partial normalization of T lymphocyte subsets and limited reduction of HIV-1 DNA despite clearance of plasma viremia.

Antiretroviral therapy commenced during primary human immunodeficiency virus type 1 (HIV-1) infection (PHI) may limit the extent of viral replication and prevent early loss of HIV-specific CD4 lymphocyte function. We studied the effect of current standard therapy (2 nucleoside analogues and a protease inhibitor) in 16 patients with symptomatic PHI. In the 13 patients who completed 1 year of treatment, plasma HIV RNA was <50 copies/mL and median CD4 cell counts were comparable to HIV-uninfected controls, with naive (CD45RA+CD62L+), primed (CD45RO+), and T cell receptor Vbeta subsets all within normal ranges. However, HIV-1 DNA levels in treated and untreated PHI patients were similar. Furthermore, CD8 cell counts remained elevated, including activated (CD38+HLA-DR+), replicating (Ki-67+), and cytotoxic (perforin+CD28-) lymphocytes. In conclusion, early antiretroviral therapy resulted in clearance of viremia and prevented loss of crucial CD4 subsets. The persistence of HIV-1 DNA together with increased CD8 T lymphocyte turnover and activation indicate continued expression of viral antigens.

Prognostic significance of Bcl-2 expression in localized squamous cell carcinoma of the head and neck.

This study was conducted to determine whether Bcl-2 overexpression in localized squamous cell carcinoma of the head and neck (SCCHN) might serve as a marker for tumors unlikely to respond to standard treatment. Tissue samples from 33 patients undergoing surgery or irradiation for early-stage SCCHN during the year 1977 to 1992 were stained for Bcl-2. All patients had either T1N0 lesions of the oral cavity, pharynx, or larynx or T1N0 or T2N0 lesions of the true vocal cords. Of the 33 patients, 26 remained disease-free after at least 3 years of follow-up; the remaining 7 patients developed either tumor recurrence or a second primary tumor, 4 of which were fatal. Twelve patients had tissue specimens staining positive for Bcl-2; 6 of these patients had a poor outcome, and 6 had a good outcome. The relationship between poor outcome and overexpression of Bcl-2 in tumor cells was statistically significant (p = .0047 by Fisher's exact test). For tumors overexpressing Bcl-2, there was no significant difference in recurrence rate between those undergoing surgery and those undergoing radiotherapy as the primary mode of treatment. The overexpression of Bcl-2 in early lesions in this study predicted a cure rate of 50%, as opposed to the generally expected 90%, suggesting that Bcl-2 is a significant prognostic indicator in early SCCHN. Future studies will determine if altering the treatment will improve outcome in these patients.

Extended temporal bone resection for squamous cell carcinoma.

OBJECTIVE: The aim of this study was to assess the surgical results of a series of patients from this unit who underwent extended temporal bone resection for recurrent squamous cell carcinoma as a salvage procedure. DESIGN: The surgical records of 15 patients were analyzed in detail. Each patient had salvage surgery in the form of an extended temporal bone resection with supraomohyoid block dissection, dural grafting, and free microvascular forearm or scalp rotation flap repair for recurrent squamous cell carcinoma in a radical mastoid cavity. RESULTS: Radical surgery yielded a 47% 5-year survival. Twenty-nine percent of the survivors had temporal lobe involvement that necessitated a partial excision of the temporal lobe of the brain. Histologic evidence of local lymph node involvement in the supraomohyoid neck dissection was present in 13% of cases. Those who died did so in the first postoperative year. All those with poorly differentiated tumors died. The survivors had well or moderately differentiated tumors. CONCLUSIONS: Radiotherapy alone or partial temporal bone resection, most commonly a radical mastoidectomy with or without preoperative or postoperative radiotherapy is used by the majority of otolaryngologists in treating squamous cell carcinoma of the temporal bone. The 5-year survival rate after this treatment remains depressingly low and the prognosis gloomy, particularly for advanced tumors. The findings in this series of extended temporal bone resections as salvage surgery in recurrent disease is encouraging, and radical surgery combined with radiotherapy from the outset may give much better 5-year survival figures in the future than the conventional partial temporal bone resection and radiotherapy.

Audio-vestibular findings in meningioma of the cerebello-pontine angle: a retrospective review.

The aim of this study was the determination of the incidence of symptoms of audio-vestibular dysfunction and of abnormalities on audio-vestibular testing in patients found to have a unilateral meningioma of the cerebello-pontine angle (CPA). The case notes of 25 patients diagnosed with unilateral, sporadic and histologically proven CPA meningioma were retrospectively reviewed. The age range of this series was 31-71 years, with a mean age of 50 years. Two patients were male (eight per cent) and 23 were female (92 per cent). The mean length of history was 44.7 months. The distribution of tumour size was skewed toward larger tumours, with 15 cases (60 per cent) having tumours with a maximum diameter greater than 3.5 cm on imaging. Pure tone audiometry was normal in five cases (20 per cent), and no patients exhibited the high frequency sensorineural hearing loss that is characteristic of vestibular schwannoma. Speech audiometry was normal in 50 per cent of cases. Caloric testing was abnormal in 77 per cent of the 18 cases tested, whilst auditory brainstem responses (ABR) were abnormal in 100 per cent of the 18 cases who had sufficient hearing for this test to be possible. The presence of normal audiometry in patients with a proven CPA lesion indicates that, if in a protocol for investigation, asymmetry of hearing is mandatory then some pathology will be missed. Any suspicion of a CPA lesion warrants investigation even in the absence of hearing loss. The investigation of choice for the identification of CPA lesions has become magnetic resonance imaging (MRI). If this technique is not available then this study indicates that ABR is a suitable and sensitive investigation. It should be borne in mind however that the data in this study has been derived from a series of predominantly large tumours, and the sensitivity of ABR to smaller CPA meningiomata may fall, as is the case for vestibular schwannoma.

Factors which influence the facial nerve outcome in vestibular schwannoma surgery.

A series of 276 patients with a unilateral vestibular schwannoma has been analysed with respect to the factors affecting post-operative facial nerve outcome. Age, tumour size, operative approach and the use of intra-operative facial nerve monitoring have been examined. The tumours were removed via either a translabyrinthine or a retrosigmoid approach. In this series increasing age and increasing tumour size were associated with a worse facial nerve outcome. The use of intra-operative facial nerve monitoring and the retrosigmoid approach were both associated with a better facial nerve outcome. Those patients having a retrosigmoid approach had a facial nerve result that was over one House grade better than those having translabyrinthine tumour removal.

The surgical management of patients with glomus tumours of the skull base.

Total surgical excision is the only treatment modality that offers a cure for patients with glomus tumours of the skull base. The vascularity, inaccessibility and frequently extensive local spread, all contribute to the difficulties encountered in the management of patients with these complex lesions. Owing to the rarity of skull base glomus tumours, experience in their management can only be attained over long periods of time. We describe the surgical management of 20 patients with large glomus tumours of the skull base treated by an otoneurosurgical team over an 11-year period. Overall, 70% of patients had an excellent outcome, 10% a good outcome and 20% a poor outcome at a mean follow-up of 3.1 years. Poor outcomes were due to severe facial nerve palsies in two cases, and poorly accommodated palsies of the bulbar cranial nerves in a further two patients. The management of postoperative neurological deficits is discussed in detail. We conclude that in the majority of patients with skull base glomus tumours, complete surgical excision can be safely achieved.

Audiovestibular results after surgery for cerebellopontine angle meningiomas.

Meningiomas are the second most common cerebellopontine angle (CPA) tumor. The reported rates of hearing preservation following surgical removal vary between 32% and 100%. There is only one recent report discussing vestibular function after CPA meningioma removal. In this series of 31 patients with CPA meningiomas, 16 patients had their tumors removed via the retrosigmoid approach. All 16 had audiovestibular assessment pre- and postsurgery and were the subjects of this study. Class A hearing is socially useful hearing and is defined as a pure tone average (PTA; average of 500 Hz and 1, 2 and 4 kHz) of < 30 dB and speech discrimination scores (SDS) of > 70%. Class B hearing is serviceable hearing, defined as PTA of < 50 dB and SDS of > 50%. Nine patients had class A hearing, and two had class B hearing presurgery. Socially useful hearing was preserved in six of nine (67%) patients in whom it was present before surgery, and serviceable or better hearing was preserved in eight of 11 (73%). Vestibular symptomatology and examination findings improved despite a decrease in the number of patients with intact caloric function postsurgery. Patients who retained vestibular function on caloric testing were symptomatically better than those who lost caloric function. These results confirm that excellent audiovestibular function is possible after CPA meningioma surgery.

The operative learning curve and its effect on facial nerve outcome in vestibular schwannoma surgery.

The successful removal of vestibular schwannomas requires a team approach by skillful and appropriately trained surgeons. It is generally perceived that the results of surgery, especially facial nerve outcome, will improve as the surgical team acquires more experience. This study of 300 patients undergoing surgical removal of vestibular schwannomas confirms that there was a significant learning curve for facial nerve outcome. In the first 50 cases, 52% had satisfactory outcomes (House grades I-III), whereas in the last 50 cases 92% had satisfactory outcomes. The major improvement came between the first 50 cases and the second 50 cases (House grades I-III results at 12 months improved from 52% to 78%). After the second 50 patients there was a gradual, but continued improvement, which is also attributable to increased surgical experience. Most of this learning curve was related to the translabyrinthine approach. House grades I-III results were attained for 45% of the first 40 and 70% of the second 40 translabyrinthine tumor removals.

Surgical results in unusual cerebellopontine angle tumours.

Vestibular schwannomas account for 84% of cerebellopontine angle (CPA) lesions. The remaining CPA tumours comprise a fascinating group of lesions which may present in a similar fashion. Fortunately, advances in neuroradiology have increased our diagnostic accuracy of these lesions. This paper describes the surgical results of a series of 69 CPA lesions which were not vestibular schwannomas. The majority of these unusual CPA tumours were meningiomas, cholesteatomas and neuromas of other cranial nerves in the posterior fossa.

The clinical significance of the communicating branches of the somatic sensory supply of the middle and external ear.

The sensory supply of the middle and external ear is complicated by multiple neural communications. The anatomy of these communications and their clinical significance will be described in this paper.